3-Drug Regimen Active in Pretreated Myeloma

Action Points

Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

A group of patients with relapsed and refractory multiple myeloma attained a 70% response rate with a three-drug combination of carfilzomib, pomalidomide, and dexamethasone.

Note that objective responses were observed across the spectrum of risk categories, and responses have proven to be durable in all patients.

NEW ORLEANS -- A group of patients with relapsed and refractory multiple myeloma attained a 70% response rate with a three-drug combination, data from a preliminary study showed.

Overall, 55 of 79 patients had objective responses to the combination of carfilzomib (Kyprolis), pomalidomide (Pomalyst), and dexamethasone. Only one of the 79 had progressive disease as best response, Jatin Shah, MD, of the University of Texas MD Anderson Cancer Center in Houston, reported here at the American Hematology Society meeting.

The heavily pretreated group had a median progression-free survival (PFS) of almost 10 months, and median overall survival had yet to be reached after 18 months.

"The combination of carfilzomib, pomalidomide, and dexamethasone is highly active in this heavily pretreated, lenalidomide (Revlimid)-refractory patient population," Shah concluded. "Response rates, progression-free survival, and overall survival were preserved independent of FISH or cytogenetic risk status. The regimen was well tolerated with no unexpected toxicities."

Despite improvements in treatment and a growing number of therapeutic options, relapsed/refractory myeloma remains a challenge. Combinations of agents with proven activity in myeloma offer one strategy to overcome the challenge.

Both carfilzomib and pomalidomide have demonstrated single-agent activity in myeloma and have different mechanisms of action to inhibit myeloma cell growth. A combination of clinical and preclinical data have suggested that combining a proteasome inhibitor and an IMiD can overcome myeloma resistance and improve response rates.

Shah and colleagues hypothesized that the combination of carfilzomib and pomalidomide plus dexamethasone would be highly active in relapsed/refractory myeloma. At the 2012 ASH meeting, investigators reported findings from a phase I study that identified the maximum tolerated dose of the three-drug combination in myeloma patients with median therapy exposure of six prior regimens.

During phase II, investigators sought to evaluate the overall response rate and safety of the three drug combination. They also wanted to assess duration of response, time to progression, PFS, time to next line of therapy, and overall survival.

Shah and colleagues planned to enroll 82 patients evaluable for efficacy, which would provide the statistical power to detect an increase in response rate from 35% to 50%. Total accrual was contingent on the regimen attaining at least 11 objective responses among the first 27 patients enrolled.

The 79 patients included in the analysis had a median age of 64, median number of prior regimens of five, and a median duration since initial diagnosis of 4.9 years.

Shah reported that 59% of the patients had a prior stem cell transplant, 89% had received bortezomib (Velcade), and all 79 had received lenalidomide and proven to be refractory. Additionally, 92% of patients in the phase I component of the study were refractory to bortezomib.

Cytogenetic assessment revealed a variety of alterations, the most common being del(13) in 34%, hyperdiploid in 32%, del(17p)/p53 in 22%, t(11;14) in 21%, hypodiploid in 11%, and t(4;14) in 10%. By mSMART risk stratification, 24% of the patients were high risk, 25% intermediate risk, and 51% low risk.

Hematologic adverse events (all grades) consisted of neutropenia in 34% of patients, anemia in 32%, thrombocytopenia in 28%, and febrile neutropenia in 4%. In general, toxicity was reversible and manageable, according to Shah.

Shah reported that 21 of 79 (27%) patients achieved a very good partial response (VGPR) with the regimen, and 34 (43%) attained partial responses. An additional 10 patients had minor responses, resulting in a clinical benefit rate of 83%. Stable disease was best response in 13 patients, and disease progression occurred in one patient.

Among patients who had partial responses or VGPR, the median duration of response was 17.7 months. Median PFS was 9.7 months, and median number of cycles of therapy was six. Analysis of overall survival is ongoing, as the median had yet to be reached at 18 months.

Objective responses were observed across the spectrum of risk categories: 14 of 18 high-risk patients, 10 of 19 intermediate-risk patients, and 28 of 38 standard-risk patients.

Responses have proven to be durable in all patients, regardless of risk category. Additionally, PFS and overall survival have been sustained without significant variation across the range of risk categories.